1. Field of the Invention
This invention relates to compositions of matter serving as topical ointment vehicles (bases) and comprising a glyceryl acetate, and an oleaginous material that can be combined with a medicament (drug substance). More particularly, it relates to ointment vehicles containing corticosteroids and methods for their use in treating skin disorders.
2. Brief Description of the Relevant Art
Ointments are one of the oldest types of vehicles for the incorporation of medicaments applied topically to treat disorders of the skin. The ointment vehicle provides a means of distributing the medication uniformly over the affected skin surface and maintaining it there for sufficient time in which the therapeutic effect can occur. Early ointment vehicles were comprised primarily of fats, greases, and petrolatum, i.e., oleaginous materials. These materials are not water washable, which detracts from cosmetic properties. They are occlusive, however, which causes skin hydration from the sweat accumulating at the skin-ointment interface and such hydration favors medicament penetration into the skin.
Most medications, especially corticosteroids, have very slight solubility in petrolatum and, therefore, must be incorporated into petrolatum as well dispersed, finely divided particles. The efficacy of medicaments in petrolatum ointment vehicles is often less than that expected from the medicament incorporated therein.
An ideal composition for a topical ointment vehicle would allow complete release of a medicament, such as a corticosteroid, from the ointment and also would achieve good penetration into the skin through occlusion or other mechanisms. Additionally, some degree of water washability would enhance the cosmetic value of the vehicle. An optimum manner of obtaining good penetration into the skin is to dissolve the medicament in the ointment vehicle or a component thereof. The medicament must not be excessively soluble in the vehicle, however, or its release from the ointment may be impeded.
The present invention seeks to remove some of the difficulties encountered with known ointment vehicles. This invention discloses the incorporation of a glyceryl acetate, preferably triacetin, into various oleaginous ointment vehicles. The use of a glyceryl acetate to dissolve the medicament alleviates the need to grind the drug substance into fine particles and to disperse the insoluble particles into the ointment vehicle, thus resulting in enhanced efficacy of the medicament. Also, vehicles of the present invention have somewhat improved water washability, when compared with petrolatum vehicles, without sacrifice of the necessary occlusive properties.
Discussion of ointment vehicles containing steroids is found in the following publications, all of which are incorporated herein by reference. U.S. Pat. No. 3,892,856 describes a steroid ointment formulation wherein the solvent for the corticosteroid is polyethylene glycol. U.S. Pat. No. 4,017,615 describes an ointment vehicle for medicaments, including anti-inflammatory steroids, containing propylene carbonate. U.S. Pat. No. 4,070,462 refers to an ointment containing esters of the steroid, betamethasone, in which a glycol solvent is used. U.S. Pat. No. 4,083,974 describes ointment and liquid preparations for anti-inflammatory steroids containing polyoxypropylene 15 stearyl ether as a solubilizing agent. U.S. Pat. No. 3,934,013 refers to pharmaceutical ointments wherein the solvents for anti-inflammatory steroids selected from the group consisting of water, glycerin, propylene carbonate, glycols, polyethylene glycol, dipropylene glycol, and mixtures thereof. U.S. Pat. No. 3,980,778 describes diflurasone diacetate ointments containing a solvent selected from the group consisting of propylene glycol, butane-2,3-diol, and 1,3-butanediol.
Triacetin (1,2,3 propanetriol triacetate; glyceryl triacetate), is listed as a pharmaceutical plasticizer, but not as a pharmaceutical solvent, in the U.S. Pharmacopeia/National Formulary 1075-76, 1492 (1985). It is also used as an antifungal drug and as a fixative in perfumery, in addition to certain industrial applications, see The Merck Index (10th ed.) p. 9407 (1983).
Triacetin and monoacetin, have been listed as one of many general pharmaceutical carriers/diluents for primarily systemic administration of specific compounds, see U.S. Pat. No. 4,543,360, and its divisional, U.S. Pat. No. 4,661,511 (for 2-(hydroxyphenyl)-indole or 2-(C.sub.2 -C.sub.6 -alkanoxyloxyphenyl)indole compounds); U.S. Pat. No. 4,218,447 (for acyl derivatives of hellebrigenin); U.S. Pat. No. 3,981,910, and its continuation-in-part, U.S. Pat. No. 4,055,653, (for sulfur-containing trialkoxybenzoylamino carboxylic acids); and U.S. Pat. No. 4,847,297 (for penicillamine). (These publications are incorporated herein by reference.)
U.S. Pat. No. 4,069,322 describes oral and topical delivery of pro-drug forms of anti-inflammatory steroids. Topical carriers listed therein include a liquid solution comprised of a pro-drug and pure triacetin.